PMP22

The PMP22 gene provides instructions for making a protein called peripheral myelin protein 22. This protein is found in the peripheral nervous system, which connects the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound.

Peripheral myelin protein 22 is a component of myelin, a protective substance that covers nerves and promotes the efficient transmission of nerve impulses. The protein is produced primarily by specialized cells called Schwann cells that wrap around and insulate nerves. Within Schwann cells, peripheral myelin protein 22 plays a crucial role in the development and maintenance of myelin. The PMP22 gene may also play a role in Schwann cell growth and differentiation (the process by which cells mature to carry out specific functions).

Before it becomes part of myelin, newly produced peripheral myelin protein 22 is processed and packaged in specialized cell structures called the endoplasmic reticulum and the Golgi apparatus. Completion of these processing and packaging steps is critical for proper myelin function.

Charcot-Marie-Tooth disease - caused by mutations in the PMP22 gene

Mutations in the PMP22 gene cause forms of Charcot-Marie-Tooth disease known as types 1A and 1E.

An extra copy of the PMP22 gene in each cell is the most common genetic change that causes type 1A Charcot-Marie-Tooth disease. The extra gene leads to an overproduction of peripheral myelin protein 22, which prevents the protein from being processed correctly. A reduced amount of functional peripheral myelin protein 22 impairs the formation of myelin. The unprocessed peripheral myelin protein 22 may also disrupt other Schwann cell activities, which leads to instability and loss of myelin (demyelination). Demyelination reduces the ability of the peripheral nerves to activate muscles used for movement or relay information from sensory cells back to the brain, causing the signs and symptoms of type 1A Charcot-Marie-Tooth disease.

Type 1A Charcot-Marie-Tooth disease is also caused by mutations that add, delete, or change the building blocks (amino acids) used to make peripheral myelin protein 22. The altered protein is probably processed at a slower rate, and some of the protein is processed abnormally. These disruptions of peripheral myelin protein 22 processing impair the normal functions of the Schwann cell, leading to demyelination and producing the signs and symptoms of type 1A Charcot-Marie-Tooth disease.

Hearing loss is experienced by some people with a form of type 1 Charcot-Marie-Tooth disease called type 1E. Type 1E is associated with particular amino acid substitutions and deletions in the PMP22 gene. The most frequently reported mutation causing hearing loss replaces the amino acid alanine with the amino acid proline at protein position 67 (also written as Ala67Pro).

hereditary neuropathy with liability to pressure palsies - caused by mutations in the PMP22 gene

Loss of one copy of the PMP22 gene from each cell is the most common genetic cause of hereditary neuropathy with liability to pressure palsies. Deletion of one copy of the PMP22 gene (also called reduced gene dosage) probably decreases the amount of peripheral myelin protein 22 available for myelin production. This disorder is also caused by PMP22 gene mutations that produce an abnormally small protein, which is rapidly broken down. Other mutations change one of the amino acids used to make peripheral myelin protein 22, producing an unstable protein. A reduction in the amount of stable protein leads to the loss of myelin. Demyelination results in increased sensitivity to pressure on the nerves, causing the signs and symptoms of hereditary neuropathy with liability to pressure palsies.